FDA Panel Rejects Diabetes Drug Citing Cancer Risks

SILVER SPRING, Md. -- An FDA advisory committee has voted 9-6 against recommending approval for the novel diabetes drug dapagliflozin. The panel has concerns about potential breast and bladder cancer risks and wants more data.

The FDA's Endocrinologic and Metabolic Advisory Committee voted Tuesday against endorsing the first-of-its-kind drug as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Dapagliflozin is an inhibitor of sodium glucose cotransporter-2 (SGLT2) which works by increasing renal glucose elimination, allowing more sugar to be excreted with urine rather than being absorbed into the bloodstream.

The committee members all praised Bristol-Myers Squibb and AstraZeneca for developing such an innovative drug that doesn't attempt to regulate insulin in the body like other diabetes treatments, but just simply flushes glucose from the body.

"To a hepatologist, it seems brilliant in its simplicity," said panelist Doris Strader, MD, associate professor of medicine at the University of Vermont.

Another bonus of the dapagliflozin: Unlike drugs that work by regulating insulin, which can cause weight gain, patients on dapagliflozin actually lost a little weight: Between an average of 2.4 lbs and 3.7 lbs, depending on the dose. (Meanwhile, patients in the control arm of the Bristol-Myers Squibb and AstraZeneca trials gained a few pounds).

The efficacy of dapagliflozin is related to glucose clearance in the kidneys, so in patients with renal impairment, the drug works less well. In a study of patients with moderate renal impairment, the drug was not found to work. The companies are recommending that dapagliflozin not be used in patients with moderate to severe renal impairment.

But the apparent efficacy of a brand new type of diabetes drug was not good enough for the panel, in light of the potential of dapagliflozin to cause breast and bladder cancers.

Across the companies' 11 clinical trials, there have been nine bladder cancers in 5,478 patients on the drug compared with one case in 3,156 controls; and there have also been nine cases of breast cancer in 2,223 women on the drug compared with just one in 1,053 female controls.

An FDA reviewer estimated that women taking dapagliflozin had a fourfold increased risk of developing breast cancer compared with those not taking the drug, and male diabetics had five times the risk for developing bladder cancer compared with the control group.

"Rates of both bladder and breast cancer are higher than what would be expected," said FDA reviewer Somya Dunn, MD, who added that the clinical trial program wasn't powered to distinguish a clinically meaningful difference in the incidence of breast or bladder cancer in the dapagliflozin arms versus the control arms.

Panelists also were concerned about one case of liver damage that was thought to be caused by dapagliflozin.

Dunn, who said, "It is difficult to make this estimate based off one case," nonetheless estimated that one in 25,000 patients exposed to dapagliflozin for at least six months would develop serious liver injury.

While the panelists said they realized the difficulty of pinpointing liver damage to a specific drug, they were worried about the potential for liver damage if dapagliflozin were to be approved, especially since it would likely be used in millions of people.

Several panelists who voted that the drug should be approved said that more breast cancers may have been detected in the dapagliflozin groups because they lost weight, making it easier to detect tumors with a mammogram. Likewise, bladder cancers may have been detected at a higher rate because dapagliflozin-treated patients were more likely to develop urinary tract infections, leading them to seek medical treatment during which the bladder cancer may have been spotted.

Because the drug causes patients to excrete more sugar, genital and bladder infections are also a side effect. Another FDA reviewer estimated that there would be one additional genital tract infection for every 24 patients treated with dapagliflozin.

Panel chairman Abraham Thomas, MD, MPH, head of endocrinology at Henry Ford Hospital in Detroit, voted in favor of the drug, arguing that it would be unreasonable for a drug company to conduct a large enough study to rule out a cancer risk. Thomas and several other panelists said the cancer risk should be studied in post-approval trials.

But Strader said she couldn't dismiss the breast and bladder cancers as "minor," and didn't want to wait until after approval to try to enroll enough patients to test whether the drug does have a link to breast and bladder cancers.

"I was concerned about the five-fold increase and the inability to explain why this happened," she said. "I know it's very hard to get these [enrollment] numbers in a pre-clinical trial but I feel very uncomfortable subjecting the diabetic population to a potentially life-threatening risk just to get more numbers."

The FDA does not have to follow the advice of its advisory committees, but it often does.

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